Candida albicans, an opportunistic yeast, is the most frequently encountered and most important fungal pathogen in the oral cavity. Because so little is known about C. albicans-host interactions, this proposal has been designed to investigate those natural host defense factors which might be involved in the regulation and control of chronic and acute oral candidiasis. In particular, basic and clinical research studies shall be utilized in this proposal to focus upon a group of histidine-rich polypeptides which are uniquely present in human saliva. Recent in vitro evidence from our laboratory has promoted us to hypothesize an antifungal role for these salivary histidine-rich polypeptides in the oral cavity. However, detailed studies outlined here are essential to develop this hypothesis and to establish the key role of histidine with its constituent imidazole group in the proposed antifungal activity. In order to aid in a determination of whether physiological concentrations of these naturally secreted molecules play a role in C. albicans disease, both in vivo oral isolates obtained from candidiasis patients and commercially available laboratory strains of C. albicans will be tested for their in vitro susceptibility to the salivary histidine-rich polypeptides and to synthetic homologous histidine peptides. Antimicrobial susceptibility testing will include both growth inhibitory turbidimetric measurements and colony forming unit viability assays. In addition, the effect of natural and synthetic histidine peptides on germ tube formation will be assessed. An in vivo clinical model system employing denture stomatitis patients will be developed to acquire information on the susceptibility of C. albicans in its native oral environment to the histidine peptides. The ability of the histidine peptides to inhibit the growth of and kill C. albicans on the denture acrylic surface will be examined and compared to the candidastatic and candidacidal activities against the corresponding C. albicans in vivo isolates of each patient. Studies will also be initiated at the ultrastructural level to gain insight into the molecular mechanism of antifungal action of the natural and synthetic histidine peptides.